Post-translational modification (PTM) of proteins is a ubiquitous form of cell signaling that orchestrates numerous processes, including metabolism, cell mobility, cell cycle, and differentiation. As a result, improper regulation of PTMs is widely implicated in aberrant development and disease. Mechanistically, PTMs provide a rapid and largely reversible means to modulate protein activity and transduce signals. Thus, the proteome and its modifications represent a rich and informative experimental plane; research that seeks to understand PTM dynamics has, and continues to, advance our understanding of fundamental biology and disease. With its high sensitivity and capacity to localize modifications to a single amino acid, mass spectrometry (MS) is well-suited to global protein PTM analysis. And MS does not require a priori knowledge of PTM sites; as such, MS has been used to catalog the complexity of various PTMs with great detail and terrific impact. That said, major challenges remain, for example, the field of proteomics almost uniformly relies on peptide cation analysis (i.e., positive electrospray) so that today's paradigm for high-throughput proteomics relies solely on the analysis of gas-phase cations. Our inability to sequence peptide anions has led to an underrepresentation of acidic portions of proteomes. This bias is exacerbated for PTMs that are chemically acidic and/or potentially labile during MS/MS, such as phosphorylation, sulfonation, carboxylation, glycosylation, and succinylation. Histidine phosphorylation (pHis), for example, accounts for ~6% of total phosphorylated proteins in eukaryotes; however, it is currently not possible to globally measure pHis as the modification is rapidly lost when pH drops below 7 (proteomic separations are routinely performed at pH 2.5-3). Here we propose new MS technology that will permit the first global analysis of proteomes in the negative ion mode. To accomplish this we shall develop the negative ion analog of electron transfer dissociation - NETD. In this approach peptide anions are oxidized by NETD reagent cations, promoting electron rearrangements that cleave the C-Ca backbone bond to produce a*- and x-type product ions for sequence interpretation.